Dense Genomewide Linkage Scan for Alcohol Dependence in African Americans: Significant Linkage on Chromosome 10

doi:10.1016/j.biopsych.2008.08.036

Biological Psychiatry

Volume 65, Issue 2, 15 January 2009, Pages 111-115

https://doi.org/10.1016/j.biopsych.2008.08.036 Get rights and content

Background

Alcohol dependence (AD) is costly to societies worldwide, moderately heritable, and genetically complex. Risk loci in several populations have been identified with genetic linkage analysis. To date, there has been no published linkage study of AD focused on African Americans (AAs).

Methods

We completed a genomewide linkage scan with approximately 6000 single nucleotide polymorphism markers to map loci increasing risk for DSM-IV AD in a set of 238 small nuclear families ascertained on the basis of multiple individuals affected with cocaine or opioid dependence. Model free linkage analysis was completed with Merlin software. A modified marker set was used to avoid bias due to markers in strong linkage disequilibrium.

Results

We identified a genomewide-significant linkage to markers near 117.2 centiMorgans on chromosome 10q23.3-24.1 (logarithm of odds score 3.32; p = 5.0E-05; empirical genomewide p = .033).

Conclusions

These data add to the growing evidence for locations for AD risk loci and provide the first linkage evidence for such a locus in the AA population.

Section snippets

Methods and Materials

Subjects for this study were recruited at four sites: Yale University School of Medicine (APT Foundation; New Haven, Connecticut), University of Connecticut Health Center (UConn; Farmington, Connecticut), McLean Hospital (Harvard Medical School; Belmont, Massachusetts), and Medical University of South Carolina (MUSC; Charleston, South Carolina). Subjects were originally ascertained for affected sibling pair linkage studies of the genetics of cocaine or opioid dependence (23, 24). Families were

Simulations

From 1000 genomewide simulations (for model-free multipoint linkage), we observed 1166 LOD scores > 1.9, 75 LOD scores > 3, 33 LOD scores > 3.32, and 2 LOD scores > 4.

Linkage Analysis

We observed one linkage peak that satisfied empirical genomewide significance criteria (i.e., on the basis of simulations); this corresponded to a maximum LOD score of 3.32 on chromosome 10 at 117.4 cM (10q23.3-q24.1) (genomewide empirical p = .033; point p = .00005) (Figure 1). The location and the value of this peak did not

Discussion

We completed a dense SNP genomewide linkage scan for the trait of DSM-IV AD in a sample of AA small nuclear families. We observed one genomewide significant linkage result, on chromosome 10, at 117.4 cM. Although we observed other linkage signals that might indicate locations of AD susceptibility genes—most notably a LOD score of 1.67 on chromosome 17—the chromosome 10 signal was by far the strongest and the only one meeting genomewide significance. This is the first report of

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Linkage is statistically quantified by calculating the logarithm of the odds (LOD) score; scores of greater than 3 are indicative of linkage between a genomic region and a phenotype. Several genome-wide linkage studies have been undertaken in families affected by alcohol dependence and other alcohol use disorders [77–85] (Table 4). However, the results are inconsistent and where evidence of linkage has been detected the LOD scores are invariably low.
The susceptibility to developing alcohol dependence and significant alcohol-related liver injury is determined by a number of constitutional, environmental and genetic factors, although the nature and level of interplay between them remains unclear. The familiality and heritability of alcohol dependence is well-documented but, to date, no strong candidate genes conferring increased risk have emerged, although variants in alcohol dehydrogenase and acetaldehyde dehydrogenase have been shown to confer protection, predominantly in individuals of East Asian ancestry. Population contamination with confounders such as drug co-dependence and psychiatric and physical co-morbidity may explain the essentially negative genome-wide association studies in this disorder. The familiality and hereditability of alcohol-related cirrhosis is not as well-documented but three strong candidate genes PNPLA3, TM6SF2 and MBOAT7, have been identified. The mechanisms by which variants in these genes confer risk and the nature of the functional interplay between them remains to be determined but, when elucidated, will undoubtedly increase our understanding of the pathophysiology of this disease. The way in which this genetic information could potentially inform patient management has yet to be determined and tested.
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Subjects were originally ascertained for genetic studies of cocaine dependence (CD) and opioid dependence (OD) using the affected sibling pair linkage approach (24,25). The recruitment procedure has been previously described in detail (26–28). Briefly, there were four recruitment sites: University of Connecticut Health Center, Yale University School of Medicine, Medical University of South Carolina, and McLean Hospital.
A genetic contribution to cannabis dependence (CaD) has been established but susceptibility genes for CaD remain largely unknown.
We employed a multistage design to identify genetic variants underlying CaD. We first performed a genome-wide linkage scan for CaD in 384 African American (AA) and 354 European American families ascertained for genetic studies of cocaine and opioid dependence. We then conducted association analysis under the linkage peak, first using data from a genome-wide association study from the Study of Addiction: Genetics and Environment, followed by replication studies of prioritized single nucleotide polymorphisms (SNPs) in independent samples.
We identified the strongest linkage evidence with CaD (logarithm of odds = 2.9) on chromosome 8p21.1 in AAs. In the association analysis of the Study of Addiction: Genetics and Environment sample under the linkage peak, we identified one SNP (rs17664708) associated with CaD in both AAs (odds ratio [OR] = 2.93, p = .0022) and European Americans (OR = 1.38, p = .02). This SNP, located at NRG1, a susceptibility gene for schizophrenia, was prioritized for further study. We replicated the association of rs17664708 with CaD in an independent AAs sample (OR = 2.81, p = .0068). The joint analysis of the two AA samples demonstrated highly significant association between rs17664708 and CaD with adjustment for either global (p = .00044) or local ancestry (p = .00075).
Our study shows that NRG1 is probably a susceptibility gene for CaD, based on convergent evidence of linkage and replicated associations in two independent AA samples.
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The lifetime prevalence rate of alcohol dependence has been estimated at 12.5–13.2% (American Psychiatric Association, 1994; Hasin et al., 2007). Numerous family, twin, and adoption studies (e.g., Allgulander et al., 1991; Goodwin et al., 1973; Heath et al., 1997; Kendler et al., 1997; Reich et al., 1988) have suggested that alcohol dependence represents a heritable condition, and a growing number of studies have performed linkage analysis to identify genomic regions associated with the disorder (e.g., Bergen et al., 2003; Gelernter et al., 2008; Hill et al., 2004; Prescott et al., 2006). Nonetheless, few loci have shown replicable evidence of association with alcohol use phenotypes across studies (Dick and Bierut, 2006; Edenberg and Foroud, 2006).
Ample data suggest that alcohol dependence represents a heritable condition, and several research groups have performed linkage analysis to identify genomic regions influencing this disorder. In the present study, a genome-wide linkage scan for alcohol dependence was conducted in a community sample of 565 probands and 1080 first-degree relatives recruited through the UCSF Family Alcoholism Study. The Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) was used to derive DSM-IV alcohol dependence diagnoses. Although no loci achieved genome-wide significance (i.e., LOD score > 3.0), several linkage peaks of interest (i.e., LOD score > 1.0) were identified. When the strict DSM-IV alcohol dependence diagnosis requiring the temporal clustering of symptoms served as the phenotype, linkage peaks were identified on chromosomes 1p36.31–p36.22, 2q37.3, 8q24.3, and 18p11.21–p11.2. When the temporal clustering of symptoms was not required, linkage peaks were again identified on chromosomes 1p36.31–p36.22 and 8q24.3 as well as novel loci on chromosomes 1p22.3, 2p24.3–p24.1, 9p24.1–p23, and 22q12.3–q13.1. Follow-up analyses were conducted by performing linkage analysis for the 12 alcohol dependence symptoms assessed by the SSAGA across the support intervals for the observed linkage peaks. These analyses demonstrated that different collections of symptoms often assessing distinct aspects of alcohol dependence (e.g., uncontrollable drinking and withdrawal vs. tolerance and drinking despite health problems) contributed to each linkage peak and often yielded LOD scores exceeding that reported for the alcohol dependence diagnosis. Such findings provide insight into how specific genomic regions may influence distinct aspects of alcohol dependence.

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Archival ReportDense Genomewide Linkage Scan for Alcohol Dependence in African Americans: Significant Linkage on Chromosome 10

Background

Methods

Results

Conclusions

Section snippets

Methods and Materials

Simulations

Linkage Analysis

Discussion

Am J Hum Genet

Am J Hum Genet

Am J Hum Genet

Biol Psychiatry

Drug Alcohol Depend

Drug Alcohol Depend

Am J Hum Genet

Am J Hum Genet

Am J Hum Genet

Am J Hum Genet

Drug Alcohol Depend

Am J Hum Genet

Am J Hum Genet

A population-based twin study of alcoholism in women

JAMA

Temperance board registration for alcohol abuse in a national sample of Swedish male twins, born 1902 to 1949

Arch Gen Psychiatry

Genetic and environmental contributions to alcohol abuse and dependence in a population-based sample of male twins

Am J Psychiatry

The genetics of alcohol intake and of alcohol dependence

Alcohol Clin Exp Res

Prevalence, correlates, disability, and comorbidity of DSM-IV alcohol abuse and dependence in the United States: Results from the National Epidemiologic Survey on Alcohol and Related Conditions

Arch Gen Psychiatry

Genome-wide search for genes affecting the risk for alcohol dependence

Am J Med Genet (Neuropsychiat Genet)

Alcoholism susceptibility loci: Confirmation studies in a replicate sample and further mapping

Alcohol Clin Exp Res

Evidence for genetic linkage to alcohol dependence on chromosomes 4 and 11 from an autosome-wide scan in an American Indian population

Am J Med Genet

Archival Report
Dense Genomewide Linkage Scan for Alcohol Dependence in African Americans: Significant Linkage on Chromosome 10